Adenosine (9-.beta.-D-ribofuranosyl-9H-purin-6-amine) was characterized in the late '20s as having hypotensive and bradycardia activity. Since then, considerable research in the molecular modification of adenosine has led to the general conclusion that cardiovascular activity is limited to analogs having intact purine and .beta.-ribofuranosyl rings.
Further research more clearly defined how the activity of these adenosine analogs affected the purinergic receptors in peripheral cell membranes, particularly the A.sub.1 and A.sub.2 receptors.
High selectivity combined with significant affinity at the A.sub.2 receptor in rat membranes was observed for certain adenosine amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine, a 14-fold A.sub.2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and in the side chain. Some of these changes led to improved A.sub.2 affinity and increased selectivity. Replacement of the phenyl moiety by a cyclohexenyl group produced a 210-fold selective agonist, whereas the cyclohexanyl analog was 530-fold selective at the A.sub.2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists. See Francis et al., J. Med. Chem., 34 2570-2579 (1991).
A series of 2-alkoxyadenosines were prepared and tested for agonist activity at the A.sub.1 and A.sub.2 adenosine receptors of the atrioventricular node and coronary arteries (vasodilation). Activities at the A.sub.1 receptor site were low and did not show a clear relationship to the size or hydrophobicity of the C-2 substituent. All the analogs were more potent at the A.sub.2 receptor, activity varying directly with the size and hydrophobicity of the alkyl group. The most potent analog in this series, 2-(2-cyclohexylethoxy)adenosine, had an EC.sub.50 of 1 nM for coronary vasodilation and was 8700-fold selective for the A.sub.2 receptor. See Ueeda et al., J. Med. Chem., 34 (4) 1334-1339 (1991).
It has now been discovered that 2-hydrazono-adenosines display superior selectivity as coronary vasodilators and A.sub.1 AR agonists.